Compounds as inhibitors of sodium channels

Abstract

Methods and small molecule compounds for inhibition of sodium channels are provided. One example of a class of compounds that may be used is represented by the compound of Formula (I) or a pharmaceutically acceptable salt, N-oxide or solvate thereof, wherein A, B, D, R, R1, R′1, R2, R3, R4, R5, R6, R7, R8 are as described herein.

What is claimed is: 
     
       1. A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein: 
         A, B, D are each Carbon; 
         R 1  is selected from the group consisting of methyl, trideuteromethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, (C 6 -C 24 )aryl, and (C 5 -C 24 )heteroaryl, wherein (C 6 -C 24 )aryl and (C 6 -C 24 )heteroaryl are optionally substituted with 1 or 2 R 8  substituents, wherein each R 8  substituent is independently selected from the group consisting of deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; 
         R 1 ′ is deuterium; 
         R 2  is selected from the group consisting of hydrogen, deuterium, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloheteroalkyl, 2-(C 1 -C 6 )alkoxyethyl, 2-hydroxyethyl, 2-(C 6 -C 24 )aryloxyethyl, bis(2-methoxyethyl), (C 1 -C 6 )alkoxymethyl, 2-(C 3 -C 6 )cycloalkoxyethyl, (C 6 -C 24 )aryl, and (C 6 -C 24 )heteroaryl, wherein (C 6 -C 24 )aryl and (C 6 -C 24 )heteroaryl are optionally substituted with 1 to 2 R 8  substituents selected from the group consisting of deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro and and (C 1 -C 6 )alkylsulfonyl; 
         R 3  is selected from the group consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; 
         R 4  is selected from the group consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; 
         R 5  is selected from the group consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; 
         R 6  and R 7  are independently selected from the group consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; and 
         wherein the indicated (*) carbon atom is in the R- or S-configuration. 
       
     
     
       2. The compound of  claim 1  wherein the compound is of Formula Ia: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
       
       wherein:
 R 1  is selected from the group consisting of methyl, trideuteromethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, (C 6 -C 24 )aryl, and (C 5 -C 24 )heteroaryl, wherein (C 6 -C 24 )aryl and (C 6 -C 24 )heteroaryl are optionally substituted with 1 or 2 R 8  substituents, wherein each R 8  substituent is independently selected from the group consisting of deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro, and (C 1 -C 6 )alkylsulfonyl; 
 R 1 ′ is deuterium; 
 R 2  is selected from the group consisting of hydrogen, deuterium, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloheteroalkyl, 2-(C 1 -C 6 )alkoxyethyl, 2-hydroxyethyl, 2-(C 6 -C 24 )aryloxyethyl, bis(2-methoxyethyl), (C 1 -C 6 )alkoxymethyl, 2-(C 3 -C 6 )cycloalkoxyethyl, (C 6 -C 24 )aryl, and (C 6 -C 24 )heteroaryl, wherein (C 6 -C 24 )aryl and (C 6 -C 24 )heteroaryl are optionally substituted with 1 or 2 R 8  substituents, wherein each R 8  substituent is selected from the group consisting of deuterium, halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C 2 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 6 -C 24 )arylamino, cyano, nitro and (C 1 -C 6 )alkylsulfonyl; and 
 R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen, methyl and trifluoromethyl. 
 
     
     
       3. The compound of  claim 2  wherein the compound is: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
       4. The compound of  claim 2  wherein the compound is: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
       5. The compound of  claim 1  wherein the compound salt is that of a pharmaceutically acceptable salt wherein the pharmaceutically acceptable salt is an acid addition salt from hydrochloric, hydrobromic, phosphoric, phosphonic, nitric, sulfuric, acetic, chloroacetic, dichloroacetic, trichloroacetic, triflouroacetic, oxalic, maleic, mandelic, malonic, citric, tartaric, fumaric, salicylic, methanesulfonic, benzenesulfonic, toluenesulfonic, or 2,6-dimethylbenzenesulfonic acid. 
     
     
       6. The compound of  claim 1 , wherein the compound is in the R-configuration at the indicated (*) carbon atom. 
     
     
       7. A composition comprising a compound of  claim 1  and one, two, three or more compounds independently selected from the group consisting of anesthetics, anti-arrhythmics, anticonvulsants, anti-antiarrhythmic peptides, anti-antiarrhythmic growth factors, anti-antiarrhythmic proteins, anti-antiarrhythmic drug-peptide conjugates, antibody-drug conjugates, vitamins, and nutraceuticals. 
     
     
       8. A drug delivery system for a compound of  claim 1 , wherein the drug delivery system is comprised of a component selected from the group consisting of pharmaceutically accepted polymers, collagen, modified collagens, thrombin-collagen gels, starches, modified starches, gels, hydrogels, pastes, colloids, suspensions, encapsulants, cyclodextrins, micelles, vesicles, and liposomes. 
     
     
       9. A composition comprising a compound of  claim 1  and isolated cells capable of acting on functional muscle cells, neuronal cells or cells of the central nervous system. 
     
     
       10. The composition of  claim 9  wherein the cells are progenitor cells or stem cells of induced, embryonic or adult origin. 
     
     
       11. A method of inhibiting sodium channels in animal cells found in living organisms or in isolated tissue cells comprising the step of contacting said cells with an effective amount of a compound of  claim 1 . 
     
     
       12. The method of  claim 11  wherein inhibition of said sodium channels in animal cells modulate membrane potential, action potential or physiological function wherein the animal cells are those of heart, brain, muscle, or central nervous system, or are peripheral cells. 
     
     
       13. The method of  claim 12 , wherein the heart, brain, muscle, central nervous system, or peripheral cells are mature cells or progenitor cells. 
     
     
       14. The method of  claim 13  wherein the progenitor cells are stem cells of induced, embryonic or adult origin. 
     
     
       15. A method of inhibiting sodium channels in mammalian cells comprising the step of co-contacting the mammalian cells with an effective amount of a compound of  claim 1  and an effective amount of an anti-arrhythmic drug. 
     
     
       16. The method of  claim 15 , wherein the anti-arrhythmic drug is an ion channel inhibitor or agonist. 
     
     
       17. The method of  claim 16  wherein the anti-arrhythmic drug is a Class 1, Class 2, Class 3, Class 4 or Class 5 anti-arrhythmic drug. 
     
     
       18. A method of inducing anesthetic, anti-arrhythmic, anticonvulsant or anti-hyperexcitability therapeutic effects in a subject in need thereof comprising the steps of:
 (a) contacting isolated progenitor cells or stem cells of induced, embryonic cells or adult origin cells with an effective amount of a compound of  claim 1 , and (b) administering an effective number of cells of step (a) to the subject, 
 OR comprising the step of: 
 (a′) co-administering an effective number of isolated progenitor cells or stem cells of induced, embryonic cells or adult origin cells and an effective amount of a compound of  claim 1  to the subject. 
 
     
     
       19. A method of inducing anesthetic, anti-arrhythmic, anticonvulsant or anti-hyperexcitability therapeutic effects in a subject in need thereof comprising the steps of:
 (a) co-contacting isolated progenitor cells or stem cells of induced, embryonic cells or adult origin cells with an effective amount of a compound of  claim 1  and an effective amount of a chemical or biological agent selected from the group consisting of anesthetics, anti-arrhythmics, anticonvulsants, drugs, small molecules with ion channel antagonist effects, small molecules with ion channel agonist effects, anti-antiarrhythmic peptides, anti-antiarrhythmic growth factors, anti-antiarrhythmic proteins, anti-antiarrhythmic drug-peptide conjugates, antibody-drug conjugates, vitamins, and nutraceuticals, and 
 (b) administering an effective number of cells of step (a) to the subject, 
 OR, comprising the step of: 
 (a′) co-administering to the subject an effective number of isolated cells and an effective amount of a compound of  claim 1  and an effective amount of a chemical or biological agent selected from the group consisting of anesthetics, anti-arrhythmics, anticonvulsants, drugs, small molecules with ion channel antagonist effects, small molecules with ion channel agonist effects, anti-antiarrhythmic peptides, anti-antiarrhythmic growth factors, anti-antiarrhythmic proteins, anti-antiarrhythmic drug-peptide conjugates, antibody-drug conjugates, vitamins, and nutraceuticals. 
 
     
     
       20. A method for therapeutic modulation of a channelopathy or to induce anesthesia in a subject, comprising the step of administering an effective amount of a compound of  claim 1  to the subject. 
     
     
       21. The method of  claim 20  wherein the channelopathy is a cardiac arrhythmia or amyotrophic lateral sclerosis or seizures.